345mediator of acquired resistance to EGFR blockade and that these mutations can be
detected in a noninvasive manner.
A second study found that cetuximab, a MAb that binds the extracellular domain
of EGFR, is effective in a subset of KRAS wild-type metastatic CRC, but after an
initial response, secondary resistance invariably ensues, thereby limiting the clinical
benefi t of this drug. Further investigations showed that point mutations of KRAS
are causally associated with the onset of acquired resistance to anti-EGFR treatment
in CRC, but resistant cells remained sensitive to combined inhibition of EGFR and
mitogen-activated protein-kinase kinase (Misale et al. 2012 ). Analysis of metasta-
ses from patients who developed resistance to cetuximab or panitumumab showed
the emergence of KRAS amplifi cation in one sample and acquisition of secondary
KRAS mutations in 60 % of the cases. KRAS mutant alleles were detectable in the
blood of cetuximab-treated patients as early as 10 months before radiographic
documentation of disease progression. In summary, the results identify KRAS
mutations as frequent drivers of acquired resistance to cetuximab in CRC, indicate
that the emergence of KRAS mutant clones can be detected non-invasively months
before radiographic progression and suggest early initiation of a MEK inhibitor as
a rational strategy for delaying or reversing drug resistance.
Personalized Management of Liver Cancer
Liver cancer is the second-leading cause of cancer-related deaths worldwide, killing
600,000 people annually. If hepatocellular carcinoma (HCC), the most common
type of liver cancer, is diagnosed in its early stages, it can be treated by surgically
removing part of the liver, by liver transplantation, or by local ablation using an
electric current to destroy the cancer cells. HCC occurs mainly in men.
Astrocyte elevated gene-1 (AEG-1) is overexpressed in >90 % of human hepato-
cellular carcinoma (HCC) patients and plays a signifi cant role in mediating aggres-
sive progression of HCC. AEG-1 is known to augment invasion, metastasis, and
angiogenesis, and now has been shown to directly contributes to another important
hallmark of aggressive cancers, that is, resistance to chemotherapeutic drugs, such
as 5-FU (Yoo et al. 2009 ). AEG-1 augments expression of the transcription factor
LSF that regulates the expression of thymidylate synthase, a target of 5-FU. In addi-
tion, AEG-1 enhances the expression of dihydropyrimidine dehydrogenase (DPYD)
that catalyzes the initial and rate-limiting step in the catabolism of 5-FU. siRNA-
mediated inhibition of AEG-1, LSF, or DPYD signifi cantly increases the sensitivity
of HCC cells to 5-FU in vitro and a lentivirus delivering AEG-1 siRNA in combina-
tion with 5-FU markedly inhibited growth of HCC cells xenotransplanted in athy-
mic nude mice when compared to either agent alone. Thus AEG-1 and LSF genes
contribute to chemoresistance. Inhibition of AEG-1 can be exploited as a therapeu-
tic strategy along with 5-FU-based combinatorial chemotherapy for HCC.
IntegraGen is developing a panel of biomarkers, which have been shown to be
prognostic for outcomes in patients with hepatocelluar carcinoma (liver cancer). By
studying the expression of genes, IntegraGen aims to better predict survival
Personalized Management of Cancers of Various Organs